Gestational hypertension in atrial natriuretic peptide knockout mice and the developmental origins of salt-sensitivity and cardiac hypertrophy

Objective

To determine the effect of gestational hypertension on the developmental origins of blood pressure (BP), altered kidney gene expression, salt-sensitivity and cardiac hypertrophy (CH) in adult offspring.

Methods

Female mice lacking atrial natriuretic peptide (ANP −/−) were used as a model of gestational hypertension. Heterozygous ANP +/− offspring was bred from crossing either ANP +/+ females with ANP −/− males yielding ANP +/−^WT offspring, or from ANP −/− females with ANP +/+ males yielding ANP +/−^KO offspring. Maternal BP during pregnancy was measured using radiotelemetry. At 14 weeks of age, offspring BP, gene and protein expression were measured in the kidney with real-time quantitative PCR, receptor binding assay and ELISA.

Results

ANP +/−^KO offspring exhibited normal BP at 14 weeks of age, but displayed significant CH (P < 0.001) as compared to ANP +/−^WT offspring. ANP +/−^KO offspring exhibited significantly increased gene expression of natriuretic peptide receptor A (NPR-A) (P < 0.001) and radioligand binding studies demonstrated significantly reduced NPR-C binding (P = 0.01) in the kidney. Treatment with high salt diet increased BP (P < 0.01) and caused LV hypertrophy (P < 0.001) and interstitial myocardial fibrosis only in ANP +/−^WT and not ANP +/−^KO offspring, suggesting gestational hypertension programs the offspring to show resistance to salt-induced hypertension and LV remodeling. Our data demonstrate that altered maternal environments can determine the salt-sensitive phenotype of offspring.